In this competing renewal, we propose to continue the largest cohort study of young men who have sex with men (YMSM) ever conducted. The RADAR study was launched in 2014 to provide critical insights into risk and protective factors for HIV and drug use, and to identify facilitators and barriers to the implementation of an effective strategy to end the epidemic. RADAR is reflective of the US HIV epidemic; it focuses on the ages with the highest HIV incidence, has exceptional representation of minority HIV disparity groups (38% black, 30% Latino), and is located in Chicago, an urban epicenter of the HIV and drug epidemics (i.e., Cook County was 4th in HIV incidence-2017). During our initial grant period, we were extremely productive in recruitment (N>1,200), retention (>80%), scientific outputs (40+ publications), training future scholars, and serving as a platform for innovative research (25+ connected studies; 7 concepts via NIDA C3PNO consortium). YMSM account for nearly 70% of all new HIV diagnoses among adolescents and young adults each year in the U.S. While all other risk groups have declining incidence, dramatic increases continue among YMSM of color. In an era of evolving prevention and treatment options, YMSM still show insufficient PrEP utilization and fall off the HIV care cascade at high rates. Substance use and minority stressors, with associated social, structural, and biological processes, are key factors that drive disparities. In response to RFA-DA-20-005 we propose a sophisticated multilevel research design, in which we will enhance the cohort in 2020 with 300 new 16-20 year olds and continue to follow existing cohort members. In this renewal, we will answer critical new questions about the HIV and substance use epidemics in YMSM. First (Aim 1), we will keep a pulse on emerging trends in drug use, HIV risk/preventive behaviors, and care continuum engagement. We will chart YMSM developmental trajectories of drug use into adulthood, with a novel focus on how use trajectories and transitions are associated with drug consequences. Further, enrollment of multiple samples of 16-20 year olds (2008, 2011, 2015, 2020) allows us to disentangle historical (e.g., advent of PrEP; marijuana legalization) and developmental changes in substance use, HIV risk and care. Next (Aim 2), we will continue to enroll cohort members? new serious partners. We will extend our prior work by longitudinally examining the key role that dyadic processes play in the development of substance use problems and HIV risk behaviors and transmission among coupled YMSM. Third (Aim 3), we will build on our provocative findings of high levels of systemic inflammation in the RADAR cohort regardless of HIV status by collecting pathogenic biomarkers of substance use to begin forecasting later-life morbidities for HIV+ and HIV- YMSM. Finally (Aim 4), RADAR will continue to add specimens and data to our well-characterized biobehavioral repository to provide a platform for high-impact science. RADAR is a unique multilevel and longitudinal study of diverse YMSM?its continuation will provide critical data to inform strategies to end the HIV epidemic.